The completion of the human genome sequence provides a powerful framework for elucidating the functional elements of the genome. In the previous funding period we have established the Yale Center of Excellence in Genomic Sciences (CEGS) and developed a number of new genomic tiling array technologies for identifying transcribed sequences, transcription-factor binding sites, and sequence variation on a large scale. Here we propose to extend these efforts and build innovative molecular and informatics approaches to elucidate genome transcription and regulation. In particular, we will improve and develop methods for identifying transcribed regions, including those that encode 5'and 3'ends, and use the resulting data to refine genome annotation. We will improve technologies for mapping many transcription factor binding sites, and we will develop novel approaches for analyzing the co-association between multiple factors. We will develop methods for explicitly linking the sequences of regulatory sites to the proteins that bind them and novel approaches for detecting the associations of sequences that are physically linked, but distantly located in the nucleus. These technologies will be applied to analysis of key regulatory steps involved in inflammation to help us understand this important process. Moreover, the technologies, data, material and tools generated from this Center are expected to have high impact for the scientific community. The Center will continue to serve as a focal point for the training of middle and high school students and their teachers, and for undergraduates, graduate students and postdoctoral fellows and for formal classroom training of undergraduate and graduate students. Through outreach programs and collaborations, the center will also enhance the genomics capabilities of other researchers at Yale and in the general scientific community.